Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Yi Zhao,Yiqing Cai,Xiangxiang Zhou,Shuai Ren,Xin Wang,Yang Han,Juan Yang,Jiarui Liu,Shunfeng Hu

doi:10.1038/s41419-021-03919-x

Abstract

Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid neoplasm and constitutes 25–35% of non-Hodgkin lymphoma [1]
Chk1 and Chk2 are the kinases downstream of ATR and ATM, and they were shown to be phosphorylated at the Ser317 and Thr68 sites, respectively (Fig. 3c). These data suggest that DLBCL cells treated with CFI-400945 show increased unrepaired DNA damage, and offer a therapeutic approach that can be combined with genotoxic agents
Since Polo-like kinase 4 (PLK4) is involved in mitotic entry and exit, we examined the effects of CFI-400945 and in vivo We explored the cytotoxic potential of CFI-400945 in combination with doxorubicin, a frontline genotoxic agent in DLBCL

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid neoplasm and constitutes 25–35% of non-Hodgkin lymphoma [1]. DLBCL is a phenotypically and genetically heterogeneous disease which has a variable response to therapy [2, 3]. The clinical needs for identifying new molecular biomarkers predicting chemosensitivity and more effective targeted cancer therapeutics remain unmet. Therapies targeting mitosis have been widely used in cancer for decades. Microtubules-targeting agents, which disrupt microtubule dynamics and block mitotic progression, are the most important antimitotic drugs used in the clinical treatment of both solid tumors and hematological malignancies [4, 5]. The clinical utility of microtubules-targeting agents is limited due to severe adverse effects and drug resistance [6]. Inhibitors of mitotic kinase have emerged as efficacious alternative treatment options for patients with solid tumors. Several mitotic kinases including cyclin-dependent kinases, aurora kinases, spindle assembly checkpoint kinases, and polo-like kinases (PLKs) were identified as strong candidates for therapeutic targets [7, 8]

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Results

Conclusion